C. difficile is a Gram-positive anaerobic bacterium that is one of the most important causes of antibiotic-associated diarrhoea in the developed world, leading to significant morbidity and mortality and placing a considerable economic burden on healthcare systems. Occurrence of diarrhoea in hospitalised patients who receive antibiotics ranges from 3% to 29%. C. difficile has been implicated as the causative organism in 10-25% of patients with antibiotic-associated diarrhoea, 50-75% of those with antibiotic-associated colitis, and 90-100% of those with antibiotic-associated pseudomembranous colitis.
The organism causes a range of intestinal diseases collectively referred to as C. difficile infections (CD) or C. difficile associated disease (CDAD). This disease can range from mild self-limiting diarrhoea, through to moderately severe diarrhoea that can lead to more serious complications including pseudomembraneous colitis and toxic megacolon, which is fatal in approximately one-third of afflicted patients. Unlike other enteric pathogens, disease is almost always associated with antimicrobial therapy or an alteration to the endogenous gastrointestinal microbiota. Mortality of C. difficile-associated disease ranges from 6% to 30% when pseudomembranous colitis is shown to be present and is substantial even in the absence of colitis.
Although CDAD has been an ongoing problem in hospitals since the introduction of antibiotics, there has been an astonishing increase in the rate and prevalence of CDI in the past decade, resulting in major epidemics in many parts of the world, including the UK, USA, Canada and mainland Europe. Furthermore, the proportion of patients who have severe, refractory, or recurrent disease has increased over the last decade.
These worldwide epidemics are largely due to the emergence of strains of increased virulence, or ‘hypervirulent’ isolates, belonging to the BI/NAP1/027 category. These strains are resistant to fluoroquinolones, and are associated with more severe disease and higher mortality rates. C. difficile now also causes disease in those previously not at risk, such as children and pregnant women, with community-associated C. difficile disease being increasingly common.
Treatment of CDAD has historically involved the use of vancomycin, metronidazole, and a combination of vancomycin and metronidazole, however there have been notable treatment failures and recurrences in a large number of published studies of antibiotic efficacy.
Importantly, CDAD recurs after treatment in 8-50% of cases.
Accordingly, there remained significant problems to be overcome in the design of an efficacious treatment for C. difficile associated disease. It is an aspect of the present invention to provide compositions and methods for the prevention and treatment of CDAD.